Improved glycemic control can delay and possibly prevent the development of some of the long-term microvascular and, perhaps, macrovascular complications of both type 1 and type 2 diabetes (The Diabetes Control and Complications Trial Research Group, N Engl J Med 329: 977-986 (1993) and UK Prospective Diabetes Study Group, Lancet 352: 837-853 (1998); Nathan et al., N Engl J Med 353: 2643-2653 (2005)). Thus, improving day-to-day glycemic control in diabetes is one of the main goals of current therapy.
The current accepted method of monitoring glycemic control is by measuring the relative concentration of glycated red-cell hemoglobin, also known as hemoglobin A1C (HbA1C), wherein high levels of HbA1C typically indicate poor glycemic control. Glycation of hemoglobin involves the non-enzymatic covalent attachment of multiple glucose molecules to the amino terminal and internal lysine residues in the hemoglobin A molecule (Bunn, Schweiz Med Wochenschr 111: 1503-1507 (1981); Bunn et al., Prog Clin Biol Res 60: 83-94 (1981); Gabbay et al., J Clin Endocrinol Metab 44: 859-864 (1977); and Shapiro et al., Metabolism 28: 427-430 (1979)). Glycation results in electrophoretic and other changes in the behavior of the hemoglobin molecule such that its concentration as a fraction of the total hemoglobin can be readily measured.
It has been shown that the relative concentration of HbA1C as compared to total hemoglobin concentration reflects the glycemic control of a patient over a period of several months, presumably based on the lifetime of the erythrocyte in the circulation of approximately 120 days. However, measurement of HbA1C provides an imperfect index of glycemic control. Due to the relatively long period of time reflected in a single HbA1C measurement, acute modifications in glycemic control do not result in rapid changes in HbA1C levels. Also, HbA1C levels can be affected by artifacts caused by conditions such as thalassemia, uremia, and hypertriglyceridemia, as well as by drugs or other ingested substances, such as aspirin, penicillin, and ethanol.
Furthermore, HbA1C measurements are relatively insensitive to minor changes in glucose tolerance, which are now viewed as predictors of diabetes development (Rohlfing et al., Diabetes Care 23: 187-191 (2000)). Moreover, the incidence of cardiovascular disease appears to be linked to concentrations of HbA1C within the conventional “normal” range, even in the absence of known diabetes (de Vegt et al., Diabetologia 42: 926-931 (1999)).
Due to the limitations of the HbA1C assay, attempts have been made to develop new biomarkers of glycemic control. For instance, fructosamine, 1,5-anhydroglucitol (1,5AG), and albumin have been tested as a glycemic control markers (Armbruster, Clin Chem 33: 2153-2163 (1987); Nowatzke et al., Clin Chim Acta 350: 201-209 (2004); (Kouzuma et al., Clin Chim Acta 324: 61-71 (2002)). However, none of these biomarkers have gained widespread use.
Accordingly, there is a need for new methods and compositions that can be used to monitor glycemic control or detect abnormal glycemic control associated with the onset or progression of diabetes. The invention provides such methods and compositions.